| Disease | TWO RANDOMIZED, TWO-PHASE CROSSOVER STUDIES WERE PERFORMED-STUDY I WITH ATORVASTATIN IN 12 HEALTHY VOLUNTEERS AND STUDY II WITH PRAVASTATIN IN 11 HEALTHY VOLUNTEERS. IN BOTH STUDIES, VOLUNTEERS TOOK 200 ML DOUBLE-STRENGTH GRAPEFRUIT JUICE OR
WATER 3 TIMES A DAY FOR 2 DAYS, ON DAY 3, EACH SUBJECT INGESTED A SINGLE 40 MG DOSE OF ATORVASTATIN(STUDY I) OR PRAVASTATIN(STUDYII) WITH EITHER 200 ML GRAPEFRUIT JUICE OR WATER, AND AN ADDITIONAL 200 ML WAS INGESTED 1/2 H AND 1 1/2 H LATER.
IN ADDITION, SUBJECTS TOOK 200 ML GRAPEFRUIT JUICEOR WATER, 3 TIMES A DAY ON DAYS 4 AND 5 IN STUDY I. IN STUDY I, SERUM CONCENTRATIONS OF ATORVASTATIN ACID, ATORVASTATIN LACTONE, 2-HYDROXYATORVASTATIN ACID, 2-HYDROXYATORVASTATIN LACTONE, AND
ACTIVE AND TOTAL 3-HYDROXY-3-METHYLGLUTARYL COENZYME A(HMG-COA) REDUCTASE INHIBITORS WERE MEASURED UP TO 72 HOUR. IN STUDY II, PRAVASTATIN, PRAVASTATIN LACTONE, AND ACTIVE AND TOTAL HMG-COA REDUCTASE INHIBITORS WERE MEASURED UP TO 24 HOURS.
GRAPEFRUIT JUICE INCREASED THE AREA UNDER THE SERUM CONCENTRATION-TIME CURVE OF ATORVASTATIN ACID FROM TIME ZERO TO 72 H[AUC(0.72)] 2.5-FOLD (P<.01), WHEREAS THE PEAK SERUM CONCENTRATION(CMAX) WAS NOT SIGNIGICANTLY CHANGED. THE TIME OF THE
PEAK CONCENTRATION (TMAX) AND THE ELIMINATION HALF-LIFE(T 1/2) OF ATORVASTATIN ACID WERE INCREASED (P<.01). THE AUC(0.72) OF ATORVASTATIN LACTONE WAS INCREASED 3.3-FOLD(P<.01) AND THE CMAX 2.6-FOLD (P<.01) BY GRAPEFRUIT JUICE, AND THE TMAX AND
T 1/2 WERE ALSO INCREASED (P<.05). GRAPEFRUIT JUICE DECREASED THE CMAX (P<.001) AND AUC(0.72)(P<.001) OF 2-HYDROXYATORVASTATIN ACID AND INCREASED ITS TMAX AND T 1/2 (P<.01). GRAPEFRUIT JUICE ALSO DECREASED THE CMAX (P<.001) AND AUC(0.72)(P<.05)
OF 2-HYDROXYATORVASTATIN LACTONE, THE AUC(0.72) VALUES OF ACTIVE AND TOTAL HMG-COA REDUCTASE INHIBITORS WERE INCREASED 1.3-FOLD (P<.05) 1.5-FOLD (P<.01), RESPECTIVELY, BY GRAPEFRUIT JUICE. IN STUDY II, THE ONLY SIGNIFICANT CHANGE OBSERVED IN THE
PHARMACOKINETICS OF PRAVASTATIN WAS PROLONGATION OF THE TMAX OF ACTIVE HMG-COA REDUCTASE INHIBITORS BY GRAPEFRUIT JUICE(P<.05). CONCLUSION: GRAPEFRUIT JUICE SIGNIFICANTLY INCREASED SERUM CONCENTRATIONS OF ATORVASTATIN ACID, ATORVASTATIN LACTONE
AND ACTIVE AND TOTAL HMG-COA REDUCTASE INHIBITORS, PROBABLY BY DECREASING CYP3A4-MEDIATED FIRST-PASS METABOLISM OF ATROVASTATIN IN THE SMALL INSTESTINE. ON THE OTHER HAND, GRAPEFRUIT JUICE HAD NO EFFECT ON THE PHARMACOKINETICS OF PRAVASTATIN. |